Use of 1-hydroxy-2-pyridones for the treatment of seborrheic dermatitis

ABSTRACT

Compounds of the formula (I) are disclosed and are suitable for the treatment of seborrheic dermatitis.

RELATED APPLICATIONS

This application is a continuation application of U.S. application Ser.No. 10/606,229, filed Jun. 26, 2003, which is a divisional of U.S.application Ser. No. 09/077,194, filed Dec. 4, 1998, which is a U.S.National Stage of International Application No. PCT/EP97/05070 filedSep. 16, 1997, which are herein incorporated by reference.

Seborrheic dermatitis is understood as meaning a disorder of the scalpwhich differs from simple dandruff by the presence of erythema as a signof inflammation, by the greater degree of scaling with occasionalitching and burning, and by the occurrence of eczematous changes toother body sites. It can occur in the form of patches, but also morefrequently affects the whole scalp and often includes, beyond thehairline, the forehead, around the neck and the ears. In severe cases,the scalp can have a secondary infection, and the changes can thenexhibit a spongy consistency, vesicle and crust formation and can weep.

Seborrheic dermatitis frequently occurs even in infancy and usuallyremits spontaneously at an age of 8-12 months. The scalp changesconsisting of erythema, scaling and occasionally vesicles and crusts ininfants can regress spontaneously within a few weeks, intermittentlyreoccur or persist during the entire childhood. They are frequentlycombined with a similar process around the eyelids, nose and ears.Later, the condition usually occurs after puberty and can last for thewhole life or even increase in strength. Approximately 1-3% of thepopulation are affected by this illness.

It is known that 1-hydroxy-2-pyridones and their salts exhibit activityagainst normal dandruff which is characterized by a clinicallynoninflammatory scaling of the scalp occurring in nearly all people (DE22 34 009).

The most promising type of treatment of seborrheic dermatitis until nowwas the topical application of corticosteroid preparations, but morerecently topical therapy with antimycotic substances has gained,importance.

While corticosteroid preparations display their activity exclusively viaan effect on the inflammatory process, the antimycotic substances suchas ketoconazole are active exclusively against the yeast fungi of thestrain Pityrosporum which is assumed to be the cause of seborrheicdermatitis. The 1-hydroxy-2-pyridones according to the invention,however, combine the properties of both classes of substance in onesubstance and exhibit both anti-inflammatory action and antimycoticactivity against Pityrosporum strains.

In comparison to ketoconazole, the substances according to theinvention—even after only a short topical contact time—concentraterapidly in the skin layers which are relevant for fungal growth and thuscontribute to a rapid cure.

While, ketoconazole is inactive in vitro against gram-positive bacteria(Kinsman et al., J. Med. Microbiol. (1983) 16, No. 2, IV), thehydroxy-pyridones according to the invention exhibit activity againstgram-positive and gram-negative aerobic, and anaerobic bacteria (Dittmaret al., Arzneim.-Forschung, (1981) 31 (II), No. 8a, pp. 1317-1322): Withrespect to the treatment of secondarily infected cases, this is anextremely important finding.

Compared with ketoconazole, the compounds used according to theinvention furthermore have very crucial advantages with respect to theirprocessing possibilities in pharmaceutical preparations. On account oftheir solubility in water, alcohols and aqueous-alcoholic solutions, thepreparation of hair lotions and transparent gel preparations is possiblewithout problems.

The preparations according to the invention can also be employed for thetreatment of Pityriasis versicolor, a superficial, noninflammatory skinfungus disorder on the trunk.

The invention therefore relates to the use of 1-hydroxy-2-pyridones ofthe formula I

in which R¹, R² and R³, which are identical or different, are a hydrogenatom or alkyl having 1-4 carbon atoms, and R⁴ is a saturated hydrocarbonradical having 6 to 9 carbon atoms or a radical of the formula II

where

-   X is S or 0-   Y is a hydrogen atom or up to 2 halogen atoms such as chlorine    and/or bromine,-   Z is a single bond or the bivalent radicals 0, S, —CR²—(R═H or    (C₁-C₄)-alkyl) or other bivalent radicals having 2-10 carbon and, if    appropriate, oxygen and/or sulfur atoms linked in the form of a    chain, where—if the radicals contain 2 or more oxygen and/or sulfur    atoms—the latter must be separated from one another by at least 2    carbon atoms and where 2 adjacent carbon atoms can also be linked to    one another by a double bond and the free valences of the carbon    atoms are saturated by H and/or (C₁-C₄)-alkyl groups,-   Ar is an aromatic ring system having up to two rings which can be    substituted by up to three radicals from the group consisting of    fluorine, chlorine, bromine; methoxy, (C₁-C₄)-alkyl, trifluoromethyl    and trifluoromethoxy, in free or in salt form,    for the production of a pharmaceutical for the treatment of    seborrheic dermatitis.

In the radicals “Z”, the carbon chain members are preferably CH₂ groups.If the CH₂ groups are substituted by C₁-C₄-alkyl groups, CH₃ and C₂H₅are preferred substituents. Exemplary radicals “Z” are:

—O—, —S—, —CH₂—, —(CH₂)_(m)— (m=2-10), —C(CH₃)₂—, —CH₂O—, —OCH₂—,—CH₂S—, —SCH₂—, SCH(C₂H₅)—, —CH═CH—CH₂O—, —O—CH₂—CH═CH—CH₂O—,—OCH₂—CH₂O—, —OCH₂—CH₂CH₂O—, —SCH₂CH₂S— —SCH₂CH₂CH₂CH₂O—,—SCH₂CH₂OCH₂C₂O—, —SCH₂CH₂OCH₂CH₂O—CH₂CH₂S— or —S—CH₂—C(CH₃)₂—CH₂—S—.

The radical “S” is a sulfur atom, the radical “O” is an oxygen atom. Theterm “Ar” denotes phenyl or fused systems such as naphthyl,tetrahydronaphthyl and indenyl, and also isolated systems as such, whichare derived from biphenyl, diphenylalkanes, diphenyl ethers and diphenylthioethers.

In the formula I, the hydrocarbon radial R⁴ is an alkyl or cyclohexylradical which can also be bonded to the pyridone ring via a methylene orethylene group or can contain an endomethyl group. R⁴ can also be anaromatic radical which, however, is preferably bonded to the pyridoneradical via at least one aliphatic carbon atom:

Important representatives of the class of compounds characterized by theformula I are:

6-[4-(4-chlorophenoxy)phenoxymethyl]-1-hydroxy-4-methyl-2-pyridone,6-[4-(2,4-dichlorophenoxy)phenoxymethyl]-1-hydroxy-4-methyl-2-pyridone,6-(biphenyl-4-oxymethyl)-1-hydroxy-4-methyl-2-pyridone,6-(4-benzylphenoxymethyl)-1-hydroxy-4-methyl-2-pyridone,6-(4-(2,4-dichlorobenzyloxy)phenoxymethyl]-1-hydroxy-4-methyl-2-pyridone,6-[4-(4-chlorophenoxy)phenoxymethyl]-1-hydroxy-3,4-dimethyl-2-pyridone,6-[4-(2,4-dichlorobenzyl)phenoxymethyl]-1-hydroxy-3,4-dimethyl-2-pyridone,6-[4-cinnamyloxy)phenoxymethyl]-1-hydroxy-4-methyl-2-pyridone,1-hydroxy-4-methyl-6-[4-(4-trifluoromethylphenoxy)phenoxymethyl]-2-pyridone,1-hydroxy-4-methyl-6-cyclohexyl-2-pyridone,1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2-pyridone,1-hydroxy-4-methyl-6-n-hexyl-, -6-isohexyl-, -6-n-heptyl- or-6-isoheptyl-2-pyridone, 1-hydroxy-4-methyl-6-octyl- or-6-isooctyl-2-pyridone, in particular 1-hydroxy-4-methyl-6-cyclohexylmethyl- or -6-cyclohexylethyl-2-pyridone, where the cyclohexyl radicalcan in each case also carry a methyl radical,1-hydroxy-4-methyl-6-(2-bicyclo[2,2,1]heptyl)-2-pyridone,1-hydroxy-3,4-dimethyl,-6-benzyl- or -6-dimethylbenzyl-2-pyridone or1-hydroxy-4-methyl-6-(β-phenylethyl)-2-pyridone.

The term “saturated” in this case designates those radicals whichcontain no aliphatic multiple bonds, i.e. no ethylenic or acetylenicbonds.

The abovementioned compounds of the formula I can be employed either infree form or as salts, use in free form is preferred.

If organic bases are used, poorly volatile bases are preferablyemployed, for example low molecular weight alkanolamines such asethanolamine, diethanolamine, N-ethylethanolamine,N-methyldiethanolamine, triethanol amine, diethylaminoethanol,2-amino-2-methyl-n-propanol, dimethylaminopropanol,2-amino-2-methylpropanediol, triisopropanolamine. Further poorlyvolatile bases which may be mentioned are, for example, ethylenediamine,hexamethylenediamine, morpholine, piperidine, piperazine,cyclohexylamine, tributylamine, dodecylamine, N,N-dimethyldodecylamine,stearylamine, oleylamine, benzylamine, dibenzylamine,N-ethylbenzylamine, dimethylstearylamine, N-methylmorpholine,N-methylpiperazine, 4-methylcyclohexylamine, N-hydroxyethylmorpholine.The salts of quaternary ammonium hydroxides such astrimethylbenzylammonium hydroxide, tetramethylammonium hydroxide ortetraethylammonium hydroxide can also be used, furthermore guanidine andits derivatives, in particular its alkylation products. However, it isalso possible to employ as salt-forming agents, for example, lowmolecular weight alkylamines such as methylamine, ethylamine ortriethylamine. Suitable salts for the compounds to be employed accordingto the invention are also those with inorganic cations, for examplealkali metal salts, in particular sodium, potassium or ammonium salts,alkaline earth metal salts such as, in particular, the magnesium orcalcium salts, as well as salts with bi- or tetravalent cations, forexample the zinc, aluminum or zirconium salt.

The active compounds to be employed in the preparations of the compoundof the formula I can be prepared, for example, according to processesgiven in U.S. Pat. No. 2,540,218.

For the use according to the invention of the compounds mentioned,liquid to semisolid pharmaceutical preparations, in particular hairlotions, shampoos, liquid soaps, as well as cream, ointment and gelpreparations, are suitable.

In this case, these are always preparations which, depending on theiractual intended use, are applied to the skin and/or to the scalp for ashorter or longer time. Due to the addition of the compounds accordingto the invention, an effective treatment of the seborrheic dermatitis isbrought about.

If the preparations according to the invention are present as shampoo,they can be in clear liquid or opaque liquid for, in cream form or evengelatinous. The surfactants on which these shampoos are based can be ofanionic, cationic, nonionic or amphoteric nature and can-also be presentas a combination of these substances.

Preferably, however, anionic surfactants are employed on their own or asa mixture with other anionic surfactants as base surfactants—ifappropriate with addition of amphoteric surfactants as cosurfactant.

As the sole detergent substances, amphoteric surfactants are virtuallyinsignificant, since their foaming behavior, thickenability and partlyalso skin and eye mucous membrane tolerability are only moderate. Incombination with various anionic surfactants, however, precisely theseproperties are synergistically improved. This explains the relativelygreat importance of the amphoteric surfactants for the optimization ofanionic shampoo bases.

Nonionic surfactants can also be employed as cosurfactants.

Examples of anionic detergent substances of this type which may bementioned are (C₁₀-C₂₀)-alkyl- and -alkylenecarboxylates, alkyl ethercarboxylates, fatty alcohol sulfates, fatty alcohol ether sulfates,alkylolamide sulfates and sulfonates, fatty acid alkylamide polyglycolether sulfates, alkanesulfonates and hydroxyalkanesulfonates,olefinsulfonates, acyl esters of isothionates, α-sulfofatty acid esters,alkylbenzosulfonates, alkylphenol glycol ether sulfonates,sulfosuccinates, sulfosuccinic acid hemiesters and diesters, fattyalcohol ether phosphates, protein-fatty acid condensation products,alkylmonoglyceride sulfates and sulfonates, alkylglyceride ethersulfonates, fatty acid methyltaurides, fatty acid sarcosinates orsulforicinoleates. These compounds and their mixtures are used in theform of their water-soluble or water-dispersible salts, for example thesodium, potassium, magnesium, ammonium, mono-, di- andtriethanolammonium as well as analogous alkylolammonium salts.

Examples of amphoteric surfactants which can be added to the shampoosare: N—((C₁₂-C₁₈)-alkyl)-β-aminopropionates and N—((C₁₂-C₁₈)-alkyl)β-iminodipropionates as alkali metal and mono-, di- andtrialkylolammonium salts; N-acylamidoalkyl-N,N-dimethylacetobetaine,preferably N—((C₈-C₁₈)-acyl)amidopropyl-N,N-dimethylacetobetaine;(C₁₂-C₁₈)-alkyl dimethylsulfopropylbetaine; amphoteric surfactants basedon imidazoline (trade name; Miranol®, Steinapon®), preferably the sodiumsalt of1-(β-carboxymethyloxyethyl)-1-(carboxymethyl)-2-laurylimidazolinium;amine oxides, e.g. (C₁₂-C₁₈)-alkyldimethylamine oxide or fatty acidamidoalkyldimethylamine oxide.

Suitable nonionic surfactants which can be employed as detergentsubstances are, for example: fatty alcohol ethoxylates (alkylpolyethylene glycols); alkylphenol polyethylene glycols; alkylmercaptanpolyethylene glycols; fatty amine ethoxylates (alkylamino polyethyleneglycols); fatty acid ethoxylates (acyl polyethylene glycols),polypropylene glycol ethoxylates (Pluronic®); fatty acid alkylolamides(fatty acid amide polyethylene glycols); sucrose esters; alkylpolyglucosides; sorbitol esters and polyglycol ether.

Suitable cationic surfactants are, for example; quaternary ammoniumsalts such as di-((C₁₀-C₂₄)-alkyl)dimethylammonium chloride or bromide,preferably di-((C₁₂-C₁₈)-alkyl)dimethylammonium chloride or bromide;(C₁₀-C₂₄)-alkyldimethylethylammonium chloride or bromide;(C₁₀-C₂₄)-alkyltrimethylammonium chloride or bromide, preferablycetyltrimethylammonium chloride or bromide and(C₂₀-C₂₂)-alkyltrimethylammonium chloride or bromide;(C₁₀-C₂₄)-alkyldimethylbenzylammonium chloride or bromide; preferably(C₁₂-C₁₈)-alkyldimethylbenzylammonium chloride;N—((C₁₀-C₁₈)-alkyl)pyridinium chloride or bromide, preferablyN—((C₁₂-C₁₆) alkyl)pyridinium chloride or bromide;N—((C₁₀-C₁₈)-alkyl)isoquinolinium chloride, bromide or monoalkylsulfate;N—((C₁₂-C₁₈)-alkylolaminoformylmethyl)pyridinium chloride;N—((C₁₂-C₁₈)-alkyl)-N-methylmorpholinium chloride, bromide ormonoalkylsulfate, N—((C₁₂-C₁₈)-alkyl)-N-methylmorpholinium chloride,bromide or monoalkyl sulfate; (C₁₆-C₁₈) alkylpentaoxethylammoniumchloride; diisobutylphenoxyethoxyethyl-dimethylbenzylammonium chloride;salts of N,N-diethylaminoethylstearylamide and -oleylamide withhydrochloric acid, acetic acid, lactic acid, citric acid, phosphoricacid; N-acylamidoethyl-N,N-diethyl-N-methylammonium chloride, bromide ormonoalkylsulfate and N-acylamidoethyl-N,N-diethyl-N-benzylammoniumchloride, bromide or monoalkylsulfate, where acyl is preferably stearylor oleyl.

The preparations according to the invention can additionally containfurther additives, e.g. aromatic substances, colorants, opacifiers andpearl luster agents, for example esters of fatty acids and polyols,magnesium and zinc salts of fatty acids, dispersions based oncopolymers, thickeners such as sodium, potassium or ammonium chloride,sodium sulfate, fatty acid alkylolamides, cellulose derivatives ofnatural gums, collagen hydrolyzates, furthermore fats, oils, fattyalcohols, silicones, substances having a keratolytic and keratoplasticaction, for example sulfur, salicylic acid or enzymes.

The shampoos are prepared in a manner known per se by mixing together ofthe individual components and a further processing—if necessary—suitedto the particular type of preparation. Some of these various possiblepreparations are described by way of example in the working examples.

The preparations according to the invention can also be present in theform of aqueous and aqueous-alcoholic hair lotions, and also those ingel form and in aerosol form as spray or foam. Alcohols employed arepreferably ethanol and isopropyl alcohol.

Further preparations which may be mentioned in which the1-hydroxy-2-pyridones can be used according to the invention are, forexample, cream and ointment preparations, products which are primarilyused for the treatment of hairless head and body parts.

The preparation of all these preparations is also carried out—as alreadymentioned in the case of shampoo—in a manner known per se with additionof the active compound employed according to the invention. Of theabovementioned 1-hydroxy-2-pyridones, the preparations according to theinvention can contain one compound or even several in combination.

The pH of the preparations is in the skin-physiological range ofapproximately pH 4.5 to 6.5. Whereas, when using the compounds in saltform, the adjustment of the pH range mentioned has to be carried outusing organic acids, this measure is not necessary when using the freecompounds.

In the preparations according to the invention, the active compounds isincorporated in amounts which are customarily between approximately 0.05and approximately 10%. Within this range, the concentrations of thespecific preparations depend on their intended use. Certain preparationforms such as concentrates, which are to be diluted before use, can haveconsiderably higher concentrations.

If they are preparations which remain on the skin and on the scalp, forexample gel preparations, ointments, creams or hair lotions, lowerconcentrations will be employed, for example from about 0.05% to about,1%, preferably from 0.1 to 0.5%. In higher concentrations, they willexpediently be used when they are preparations which, optionally afterdilution, only act on the scalp for a short time, for example shampoosor liquid soaps. In these cases, for example, concentrations ofapproximately 0.2 to approximately 10%, preferably from approximately0.5% to approximately 2%, can be expedient.

The following quantitative data relate to the weight, if not statedotherwise.

EXAMPLE 1

A preparation according to the invention has the following composition:

Shampoo

(based on anionic detergent substances)1-Hydroxy-4-methyl-6-cyclohexyl-2(1H)pyridone  1.00% Sodium lauryldiglycol ether sulfate (27% strength 40.00% solution) Disodium laurylpolyglycol ethersulfosuccinate (33% 10.00% strength solution) Sodiumchloride  2.50% Water 46.50%

EXAMPLE 2

A preparation according to the invention has the following composition:

Shampoo

(based on anionic detergent substance with amphoteric surfactant ascosurfactant) 1-Hydroxy-4-methyl-6-cyclohexyl-2(1 H)pyridone  1.00%Sodium lauryl diglycol ether sulfate (27% strength 36.00% solution)Cocamidopropylbetaine (30% strength solution)  6.00% Sodium chloride 3.30% Water 53.70%

EXAMPLE 3

A preparation according to the invention has the following composition:

Shampoo

(based on anionic detergent substance with nonionic surfactant ascosurfactant) 1-Hydroxy-4-methyl-6-cyclohexyl-2(1H)pyridone  1.50%Sodium lauryl diglycol ether sulfate (27% strength 30.00% solution)Lauryl alcohol polyglucoside  8.00% Sodium chloride  2.00% Water 58.50%

EXAMPLE 4

A preparation according to the invention has the following composition:

Liquid soap 1-Hydroxy-4-methyl-6-cyclohexyl-2(1H)pyridone  1.00% Sodiumlauryl diglycol ether.sulfate (27% strength 35.00% solution)Cocamidopolyglycol ether sulfate magnesium salt (30%  8.00%strength.solution) Cocamidopropylbetaine (30% strength solution) 10.00%0 Lauryl alcohol glycol ether  2.00% Sodium chloride  2.00% Water42.00%

EXAMPLE 5

A preparation according to the invention has the following composition:

Hair lotion 1-Hydroxy-4-methyl-6-[4-(4-chlorophenoxy)phenoxy-  0.05%methyl]2(1H)pyridone 2-Propanol 60.00% Water 39.95%

EXAMPLE 6

A preparation according to the invention has the following composition:

Gel preparation 1-Hydroxy-4-methyl-6-cyclohexyl-2(1H)pyridone 0.75%2-Propano1 15.00%  2-Octyldodecanol 7.5%  Carbomer 4,000,000 0.50%Polysorbate 60 1.50% Sodium bydroxide 0.18% Water 74.57% 

EXAMPLE 7

A preparation according to the invention has the following composition:

Cream preparation 1-Hydroxy-4-methyl-6-cyclohexyl-2(1H)-pyridone, 1.00%aminoethanol salt 1:1 2-Octyldodecanol 7.5%  Liquid paraffin 7.50%Stearyl alcohol 7.50% Cetyl alcohol 7.50% Polysorbate 60 3.00% Sorbitanmonostearate 2.00% Lactic acid, 90% strength 0.51% Water 63.49% 

EXAMPLE 8

In a clinical study with a total of 180 patients, it was possible toshow that the symptoms of seborrheic dermatitis of the scalp (severescaling, inflammation, itching) can be effectively treated by a 1-2×weekly treatment with a 1% strength ciclopirox shampoo preparation overa period of 4 weeks.

EXAMPLE 9

In a clinical study, it was possible to successfully treat 180 patientswith seborrheic dermatitis of the scalp, of the face and of the upperbody by application of a 0.77% strength ciclopirox gel preparation overa period of 4 weeks.

1-13. (canceled)
 14. A method of treating seborrheic dermatitiscomprising administering to a human seborrheic dermatitis patient anamount effective for the treatment of seborrheic dermatitis of acomposition comprising only one active ingredient, the active ingredientconsisting of ciclopirox and at least one surfactant chosen from anionicsurfactants, cationic surfactants, nonionic surfactants, and amphotericsurfactants; wherein the composition has a pH ranging from about 4.5 toabout 6.5; and wherein the composition is a single composition.
 15. Amethod of treating seborrheic dermatitis as claimed in claim 14 in whichthe composition further comprises at least one additional surfactantchosen from anionic, cationic, nonionic, and amphoteric surfactants. 16.A method of treating seborrheic dermatitis comprising administering to ahuman seborrheic dermatitis patient an amount effective for thetreatment of seborrheic dermatitis of a composition comprising only oneactive ingredient, the active ingredient consisting of ciclopirox and atleast one surfactant chosen from anionic surfactants, cationicsurfactants, nonionic surfactants, and amphoteric surfactants; whereinthe composition has a pH ranging from about 4.5 to about 6.5; andwherein the composition is a single composition, which is a shampoo. 17.A method of treating seborrheic dermatitis as claimed in claim 16 inwhich the composition further comprises at least one additionalsurfactant chosen from anionic, cationic, nonionic, and amphotericsurfactants.